Department of Physiology and Biophysics Mississippi Center for Obesity ResearchMississippi Center for Heart ResearchUniversity of Mississippi Medical Center Jackson MS.
Department of Endocrinology and Metabolism West China Hospital of Sichuan University Chengdu China.
J Am Heart Assoc. 2021 Mar 16;10(6):e018298. doi: 10.1161/JAHA.120.018298. Epub 2021 Mar 13.
Background We determined if the sodium glucose co-transporter 2 inhibitor empagliflozin attenuates pressure overload-induced heart failure in non-diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4-6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction-induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate-activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate-activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure-overload in non-diabetic mellitus mice.
背景 我们旨在通过直接的心脏作用及其相关机制，确定钠-葡萄糖协同转运蛋白 2 抑制剂恩格列净是否可减轻非糖尿病小鼠的心脏压力超负荷诱导的心力衰竭。
方法和结果 雄性 C57BL/6J 小鼠（4-6 月龄）接受假手术或横主动脉缩窄术以产生心脏压力超负荷。横主动脉缩窄术后 2 周，每天给予恩格列净（10mg/kg）或载体治疗 4 周。恩格列净增加了存活率，并显著减轻了横主动脉缩窄后的左心室重构和心脏纤维化的不良影响。恩格列净还通过超声心动图评估，减轻了横主动脉缩窄诱导的心力衰竭小鼠的左心室收缩和舒张功能障碍，并使运动耐力提高了 36%。恩格列净显著增加了衰竭心脏中的葡萄糖和脂肪酸氧化，同时减少了糖酵解。尽管空腹血糖、体重或每日尿量无明显变化，但恩格列净仍具有这些有益的心脏作用。在分离的心肌细胞的体外实验中，恩格列净具有直接改善心肌收缩力和钙瞬变的作用。重要的是，分子对接分析和分离的心脏灌流实验表明，恩格列净可以与心脏葡萄糖转运蛋白结合以减少糖酵解，恢复 AMP 激活的蛋白激酶的激活，并抑制雷帕霉素靶蛋白复合物 1 途径的激活。
结论 我们的研究表明，恩格列净可能直接与葡萄糖转运蛋白结合以减少糖酵解，重新平衡糖酵解和氧化磷酸化之间的偶联，并调节 AMP 激活的蛋白激酶雷帕霉素靶蛋白复合物 1 途径，以减轻非糖尿病小鼠的压力超负荷诱导的不良心脏重构和心力衰竭进展。
